Proliferation of smooth muscle cells (SMCs) in the vessel wall is an important event in the formation of vascular lesions in atherosclerosis or in response to vascular injury. Treatment of atherosclerosis frequently includes the clearing of blocked vessels by angioplasty or endartarectomy, surgical procedures in which atherosclerotic plaques are compressed or removed through catheterization (angioplasty) or stripped away from the arterial wall through an incision (endartarectomy). These procedures remove the vascular endothelium, disturb the underlying intimal layer, and result in the death of medial SMCs. This injury is followed by medial SMC proliferation and migration into the intima, which characteristically occurs within the first few weeks after injury and stops when the overlying endothelial layer is reestablished.
In about 30% or more of patients treated by angioplasty or endartarectomy, thrombosis and/or SMC proliferation in the intima causes re-occlusion of the vessel and consequent failure of the angioplasty or endartarectomy. This closure of the vessel subsequent to surgery is known as restenosis.
A similar process of SMC proliferation has also been observed in vascular grafts and organ transplants, and may contribute to transplant rejection.
It has been postulated that growth factors, such as platelet derived growth factor (PDGF), play a role in the development of atherosclerotic plaques (reviewed by Ross et al., Cell 46: 155-169, 1986). One proposed mechanism for plaque formation is the release by platelets, at sites of endothelial denudation, of growth factors that stimulate SMC growth (Ross and Glomset, N. Eng. J. Med. 295: 369-377, 420-425, 1976; Ross, Arteriosclerosis 1: 293-311, 1981). Moore et al. (Thrombos. Haemostas. (Stuttg.) 35: 70, 1976) and Friedman et al. (J. Clin. Invest. 60: 1191-1201, 1977), using an indwelling catheter injury model, reported an inhibition of experimentally induced intimal lesion formation in rabbit arteries by prolonged thrombocytopenia induced by administration of anti-platelet serum. It has also been postulated that SMCs may themselves produce PDGF which stimulates lesion development through an autocrine mechanism (Ross et al., ibid; Walker et al., Proc. Natl. Acad. Sci. USA 83: 7311-7315, 1986). Fingerle et al. (P roco Natl. Acad. Sci. USA 86: 8412-8416, 1989) investigated intimal lesion formation in thrombocytopenic rats and concluded that platelets do not play a role in the initial SMC proliferation after balloon injury but may regulate SMC migration into the intima. Platelets are now known to release a number of growth factors, including PDGF, transforming growth factors alpha and beta (TGF.alpha. and TGF.beta.), insulin-like growth factor I (IGF-I) and platelet derived endothelial cell growth factor. However, there has been no direct evidence to demonstrate that a particular mitogen or mitogens is responsible for the development of arterial lesions.
Removal of atherosclerotic plaques by angioplasty or endartarectomy has limited efficacy, and no effective treatment for restenosis has been developed. There is therefore a need in the art for methods of reducing or preventing stenosis of blood vessels following vascular injury, such as injury due to balloon catheterization or endarterectomy, as well as in vascular grafts and organ transplants. The present invention provides such methods and fulfills other, related needs.